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Management of immune thrombocytopenia (ITP) in dogs and cats is evolving, but there are no evidence‐based guidelines to assist clinicians with treatment decisions. Likewise, the overall goals for treatment of ITP have not been established. Immunosuppressive doses of glucocorticoids are the first line treatment, but optimal treatment regimens beyond glucocorticoids remain uncertain. Additional options include secondary immunosuppressive drugs such as azathioprine, modified cyclosporine, and mycophenolate mofetil, usually selected based on clinician preference. Vincristine, human IV immunoglobulin (hIVIg), and transfusion of platelet or red blood cell–containing products are often used in more severe cases. Splenectomy and thrombopoietin receptor agonists are usually reserved for refractory cases, but when and in which patient these modalities should be employed is under debate. To develop evidence‐based guidelines for individualized treatment of ITP patients, we asked 20 Population Intervention Comparison Outcome (PICO) format questions. These were addressed by 17 evidence evaluators using a literature pool of 288 articles identified by a structured search strategy. Evidence evaluators, using panel‐designed templates and data extraction tools, summarized evidence and created guideline recommendations. These were integrated by treatment domain chairs and then refined by iterative Delphi survey review to reach consensus on the final guidelines. In addition, 19 non‐PICO questions covering scenarios in which evidence was lacking or of low quality were answered by expert opinion using iterative Delphi surveys with panelist integration and refinement. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The rigorous consensus process identified few comparative treatment studies, highlighting many areas of ITP treatment requiring additional studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Diagnosis of Immune Thrombocytopenia in Dogs and Cats. [ABSTRACT FROM AUTHOR]

Background: Veterinary hospital antimicrobial stewardship (AMS) guidelines might help combat antimicrobial resistance (AMR). Objective s : Determine the conditions and types of infection for which antimicrobial drugs (AMDs) deemed critically important (CIA) by the World Health Organization (WHO) were prescribed and assess the effect of hospital AMS guidelines on adherence to International Society for Companion Animal Infectious Diseases published guidelines for the treatment of superficial bacterial folliculitis, respiratory tract disease and urinary tract infection in these cases. Animals: Dogs and cats managed at an academic veterinary hospital from 1/21 to 6/21 and 9/21 to 6/22. Methods: Prescriptions of cephalosporins (third or fourth generation), glycopeptides, macrolides/ketolides, polymyxins, and quinolones were identified. Data on culture and susceptibility (C/S) testing and previous AMD exposure were collected. Frequencies were compared between time periods using Fisher's exact test with Bonferroni corrections. Results: In animals prescribed ≥1 WHO‐CIA AMD, fluoroquinolones were the most frequently prescribed WHO‐CIA class in dogs (567/1724, 32.9%) and cats (192/450, 42.7%). No animals were prescribed carbapenems, dihydrofolate reductase inhibitors/sulfonamides, or polymyxins. No cats were prescribed aminoglycosides or amphenicols. Institutional guidelines were followed in 57.8% (324/561) cases. The most frequent causes of nonadherence were failure to perform C/S testing 46.0% (109/237) and unnecessary use of a higher‐tier AMD 43.0% (102/237). Bacterial C/S testing was more frequently performed after AMS guideline institution (59.7% vs. 46.8%, P = 0.0006). Conclusions and Clinical Importance: Adherence to published guidelines remained poor despite an increase in C/S testing. There were no changes in the frequencies of confirmed infections, positive cultures or AMD resistance between time periods. [ABSTRACT FROM AUTHOR]

Background: Primary immune thrombocytopenia (pITP) in dogs presents a diagnostic challenge, and clinical markers of severity are lacking. Objectives: Identify clinicopathologic features that differentiate pITP from secondary ITP (sITP) and markers related to bleeding severity, transfusion, and survival of dogs with pITP. Animals: Ninety‐eight thrombocytopenic dogs (58 pITP and 40 sITP). Methods: Client‐owned dogs with platelet counts <50 000/μL were enrolled in a prospective, multi‐institution cohort study. History and treatment information, through a maximum of 7 days, was recorded on standard data forms. Bleeding severity was scored daily using a bleeding assessment tool (DOGiBAT). At‐admission blood samples were collected for CBC, biochemistry, C‐reactive protein concentration, and coagulation panels, and to measure platelet surface‐associated immunoglobulin G (PSAIg) and expression of platelet membrane proteins and phospholipids. Dogs with evidence of coincident disease were classified as sITP. Results: No definitive pITP diagnostic test was found. However, pITP cases were characterized by lower platelet counts, D dimer concentrations, and platelet membrane protein expression than sITP cases. Differentiation between pITP and sITP was further enhanced using logistic regression modeling combining patient sex, coagulation profile, platelet count, D dimer, and PSAIg. A second model of pITP severity indicated that low hematocrit and high BUN concentration were associated with non‐survival. Low hematocrit at admission, but not platelet count or DOGiBAT score, was associated with transfusion. Conclusions and Clinical Importance: Pending validation studies, models constructed from at‐admission clinicopathologic findings may improve differentiation of pITP from sITP and identify the most severe pITP cases at the time of presentation. [ABSTRACT FROM AUTHOR]

Objective: To describe a population of sick dogs administered rivaroxaban monitored with a rivaroxaban‐calibrated anti‐Xa activity assay (aXa). Design: Descriptive retrospective study. Setting: Two veterinary teaching hospitals. Animals: Client‐owned dogs administered rivaroxaban and monitored with aXa from January 2018 to January 2020 were eligible for study. Interventions: None. Measurements and Main Results: Medical records were reviewed and 19 dogs with a variety of underlying disease processes were identified. Rivaroxaban was administered to 12 of 19 dogs (63%) with confirmed thrombosis, 4 of 19 dogs (21%) with a strong clinical suspicion of thrombosis, and in 3 of 19 dogs (16%) with no current evidence of thrombosis. The median rivaroxaban dose administered was 0.96 mg/kg/day (0.62–1.58 mg/kg/day), with 15 of 19 dogs (79%) receiving rivaroxaban once daily. Clopidogrel was concurrently administered to 11 of 19 dogs (58%). Complete or partial thrombus resolution was identified in 5 of 12 (42%) and 3 of 12 (25%) dogs, respectively. Rivaroxaban appeared safe, with only 1 of 19 dogs (5%), concurrently administered clopidogrel, developing evidence of mild hematuria. Posttreatment monitoring revealed that 8 of 19 dogs (42%) had aXa below the target (aXa range of 150–250 ng/ml associated with effective treatment and prevention of venous thrombosis in people). The remaining 3 to 19 dogs (16%) achieved this range, and 8 of 19 dogs (42%) exceeded the range. No significant relationship between the initial rivaroxaban dose administered and the corresponding aXa result was identified. There were also no significant differences in baseline clinicopathological variables in dogs in which aXa fell within or outside this range. Conclusions: aXa was most commonly measured in dogs receiving rivaroxaban with confirmed or suspected thrombosis. Dogs in this study received a range of rivaroxaban dosages and attained variable aXa values that were not directly correlated with dosage. [ABSTRACT FROM AUTHOR]

Background: Prolonged antimicrobial drug (AMD) treatment is associated with antimicrobial resistance development. Biomarker measurement may aid treatment decision‐making. Objectives: Investigate temporal changes in blood biomarker concentrations in dogs undergoing treatment for pulmonary and intra‐abdominal infections; compare time to biomarker concentration normalization with duration of clinician‐directed AMD treatment. Animals: Forty‐two client‐owned dogs with pneumonia (n = 22), septic peritonitis (n = 10), or pyometra (n = 10). Methods: Plasma concentrations of C‐reactive protein (CRP), serum amyloid A (SAA), haptoglobin, procalcitonin, nucleosomes, cell‐free DNA (cfDNA), high‐mobility group box‐1 (HMGB1), CC‐motif chemokine ligand‐2 (CCL2), CXC‐motif chemokine ligand‐8 (CXCL8), and keratinocyte chemoattractant‐like (KC‐Like) were quantitated in samples collected on days 1, 3, 7, 14, 28, and 60. Treatment was directed by clinicians blinded to biomarker concentrations. Results: Concentrations of CCL2, CRP, and KC‐Like were maximal on D1, concentrations of SAA, cfDNA, HMGB1, and nucleosomes were maximal on D3 and haptoglobin concentrations were maximal on D7. These maximal concentrations were significantly different from those on D60. Concentrations of CRP and SAA decreased by 80% from peak and into respective reference intervals before AMDs were discontinued. For CRP, the median (interquartile range [IQR]) times to 20% peak and normal were 7 (6‐9) and 7 (6‐12) days, respectively, and for SAA they were 4 (4, 5) and 6 (5‐8) days, respectively, compared to a median (IQR) duration of AMD prescribing of 16 (12‐23) days (all P <.0001). Conclusions and Clinical Importance: Biomarker concentrations normalized within 7 to 14 days. Serial measurements of CRP and SAA might aid identification of disease resolution and could help guide AMD prescription decision‐making. [ABSTRACT FROM AUTHOR]

Objective: To assess the association of candidate attributes and residency training factors with success on the American College of Veterinary Emergency and Critical Care (ACVECC) board certification examination and to develop multivariable models of first‐attempt success. Design: Prospective survey‐based study. Setting: Post‐assessment ACVECC examination candidates. Animals: None. Interventions: None. Measurements and main results: Comprehensive surveys were distributed to ACVECC examination candidates in 2016 to 2018 after completion of their assessments, but prior to publication of examination results. Unique anonymous candidate identification numbers were used to match survey responses to outcome data from the office of the ACVECC Executive Secretary. After curation to retain only the first response from each candidate, there were 97 unique candidate responses available for analysis. Univariate analyses identified multiple factors associated with first‐attempt success and multiple differences between academic and private practice residency programs. Multivariable logistic regression modeling suggested that 5 factors were independently associated with first‐attempt success on the ACVECC examination, specifically younger age, more weeks of study prior to the examination, training at a facility with more ACVECC Diplomates, training at a facility with more ACVECC residents, and having no requirement to manage both Emergency Room (ER) and Critical Care (CC) cases simultaneously. Conclusions: Numerous resident and training center factors are associated with success in the ACVECC board certification examination. Residents and training centers might be able to use these data to enhance training, but caution must be exercised because these data are associative only. [ABSTRACT FROM AUTHOR]

Background: Combatting antimicrobial resistance requires a One Health approach to antimicrobial stewardship including antimicrobial drug (AMD) use evaluation. Current veterinary AMD prescribing data are limited. Objectives: To quantify companion animal AMD prescribing in primary care and specialty practice across 3 academic veterinary hospitals with particular focus on third‐generation cephalosporins, fluoroquinolones, and carbapenems. Animals Dogs and cats presented to 3 academic veterinary hospitals from 2012 to 2017. Methods: In this retrospective study, AMD prescribing data from 2012 to 2017 were extracted from electronic medical records at each hospital and prescriptions classified by service type: primary care, specialty practice or Emergency/Critical Care (ECC). Hospital‐level AMD prescribing data were summarized by species, service type, AMD class, and drug. Multivariable logistic full‐factorial regression models were used to estimate hospital, year, species, and service‐type effects on AMD prescribing. Estimated marginal means and confidence intervals were plotted over time. Results: The probability of systemic AMD prescribing for any indication ranged between 0.15 and 0.28 and was higher for dogs than cats (P <.05) apart from 2017 at hospital 1. Animals presented to primary care were least likely to receive AMDs (dogs 0.03‐0.15, cats 0.03‐0.18). The most commonly prescribed AMD classes were aminopenicillins/β‐lactamase inhibitors (0.02‐0.15), first‐generation cephalosporins (0.00‐0.09), fluoroquinolones (0.00‐0.04), nitroimidazoles (0.01‐0.06), and tetracyclines (0.00‐0.03). Among the highest priority classes, fluoroquinolones (dogs 0.00‐0.09, cats 0.00‐0.08) and third‐generation cephalosporins (dogs 0.00‐0.04, cats 0.00‐0.05) were most frequently prescribed. Conclusions and Clinical Importance: Antimicrobial drug prescribing frequencies were comparable to previous studies. Additional stewardship efforts might focus on fluoroquinolones and third‐generation cephalosporins. [ABSTRACT FROM AUTHOR]

Background: Thrombocytopenia in dogs is common in critical care medicine, but availability of fresh platelet concentrates in veterinary medicine can be limiting. Lyophilized platelets have long shelf‐lives and can be easily transported, stored, and administered in various settings. Objective: To evaluate the efficacy and safety of a novel trehalose‐stabilized canine lyophilized platelet product in thrombocytopenic dogs with clinically‐evident bleeding. Animals Eighty‐eight dogs with platelet counts <50 × 103/μL and a standardized bleeding assessment tool (DOGiBAT) score ≥2. Methods: Multicenter, randomized, non‐blinded, non‐inferiority clinical trial comparing dimethyl sulfoxide (DMSO)‐stabilized cryopreserved platelet concentrates (CPP) with trehalose‐stabilized lyophilized platelets (LP) for control of bleeding in thrombocytopenic dogs. Dogs were randomized to receive 3 × 109 platelets/kg of LP or CPP. Primary outcome measures were change in DOGiBAT score, platelet count, need for additional red cell transfusion and all‐cause mortality. Results: Fifty dogs received LP and 38 received CPP. Baseline demographics and clinical characteristics of both groups were comparable. At 1‐hour post‐transfusion, LP were superior for change in DOGiBAT score, and non‐inferior at 24‐hours post‐transfusion. The LP were non‐inferior to CPP for change in platelet count, need for additional red blood cell units, and survival to discharge. The LP were superior for change in hematocrit at 1‐hour post‐transfusion, and non‐inferior at 24‐hours. No adverse effects were noted in either group. Conclusions and Clinical Importance: A novel trehalose‐stabilized canine LP product appears to be logistically superior and is clinically non‐inferior to DMSO‐stabilized canine CPP for management of bleeding in thrombocytopenic dogs. [ABSTRACT FROM AUTHOR]

Background: Immune-mediated hemolytic anemia (IMHA) is a common disease that affects all breeds of dogs and is associated with significant morbidity and mortality. Intravascular hemolysis of erythrocytes in IMHA is caused by complement activation and is often fatal. No current treatments target complement activation in canine IMHA. Human C1 esterase (C1-INH) reduces canine complement-mediated hemolysis in vitro, and a recent pharmacokinetic analysis of an FDA licensed formulation of C1-INH in dogs confirmed that a 50 IU/kg dose of C1-INH is safe to administer to dogs, and effectively inhibits canine complement mediated hemolysis ex-vivo. The C1INCH randomized controlled trial will evaluate the efficacy of this drug in dogs with intravascular hemolysis. Methods: We will conduct a multicenter, placebo-controlled double-blind randomized clinical trial of C1-INH in dogs with intravascular hemolysis due to IMHA. We will randomize 18 dogs to receive three doses of intravenous C1-INH or saline in 24 h. Immunosuppressive and antithrombotic therapies will be standardized. Primary outcome measures will be changes in plasma free hemoglobin, serum concentrations of LDH, bilirubin, and haptoglobin. Using patient samples, we will evaluate complement activation in canine IMHA using a novel C5b-9 ELISA assay, flow cytometric detection of C3b on RBC, and by measurement of residual plasma complement activity. Secondary outcome measures will be survival to hospital discharge, duration of hospitalization, number and volume of red blood cell transfusions, and rescue therapy requirements. We will monitor dogs for adverse drug reactions. Sample size was estimated from pilot data on LDH and hemolysis index (HI) in dogs with IMHA. To detect 2-way differences between the upper and lower 50% of the LDH and HI values of equivalent size with 80% power at P < 0.05 will require 9 dogs in each arm. Discussion: We anticipate that IV administration of C1-INH will significantly inhibit complement mediated hemolysis in dogs with intravascular IMHA, as determined by blood biomarker measurements (decreased plasma hemoglobin, LDH and bilirubin, increased haptoglobin). We expect this will translate into significant reductions in transfusion requirements and duration of hospitalization. Trial registration: This trial has been prospectively registered with the AVMA registry (AAHSD005025). [ABSTRACT FROM AUTHOR]

Objective: To quantify plasma cytokine concentrations in dogs with sepsis and noninfectious systemic inflammation and to evaluate the association between plasma cytokines and outcome in dogs with sepsis. Design: Prospective, observational cohort study. Setting: University teaching hospital. Animals: Forty‐five dogs with sepsis, 10 dogs with noninfectious systemic inflammation (nSIRS), and 15 healthy controls were consecutively enrolled from June 2015 to February 2016 and followed to hospital discharge. Dogs with sepsis satisfied ≥2 SIRS criteria and had a documented or highly suspected bacterial infection. Dogs with nSIRS satisfied ≥2 SIRS criteria but had no evidence of infection. Dogs <3 kg and those with documented coagulopathy were excluded. Interventions: Measurement of inflammatory cytokines and high‐mobility group box‐1 (HMGB‐1) was performed on each group. Measurements and Main Results: High‐mobility group box‐1 concentrations were analyzed by ELISA. Plasma concentrations of 13 cytokines were measured in singlet using multiplex magnetic bead assays. Kruskal–Wallis with Dunn's multiple comparison tests were used to compare biomarker concentrations between groups. Mann–Whitney U‐tests were used to compare biomarker concentrations between survivors and nonsurvivors. Associations between biomarkers were evaluated using Spearman's correlation coefficients. Independent outcome predictors were identified using multivariable logistic regression. Alpha was set at 0.05. Concentrations of interleukin (IL)‐6, C‐X‐C motif chemokine (CXCL)‐8, keratinocyte‐derived chemokine (KC)‐like, C‐C motif chemokine ligand 2 (CCL2), and HMGB‐1 were significantly greater in dogs with sepsis versus healthy controls (all P ≤ 0.034). In dogs with sepsis, only CCL2 was independently associated with survival (odds ratio [OR] 0.996, 95% CI 0.993–0.999, P = 0.004). A cut‐off of 385 pg/mL for CCL2 was 80% sensitive and 91.4% specific for nonsurvival (area under the ROC curve [AUROC] 0.866). Conclusions: Dogs with sepsis have significantly increased concentrations of HMGB‐1 and inflammatory cytokines, including IL‐6, CXCL8, and KC‐like. Increased CCL2 concentration is a negative prognostic indicator in dogs with sepsis. These findings should be confirmed using duplicate analyses in larger, distinct populations of dogs with sepsis before applying them to clinical patients. [ABSTRACT FROM AUTHOR]

Objective: To illustrate the application of the Consensus on the Rational Use of Antithrombotics in Veterinary Critical Care (CURATIVE) guidelines to the management of dogs and cats at risk of developing thrombosis using a case‐based approach. Etiology: Dogs and cats become at risk of developing thrombosis from a wide range of conditions. These conditions often involve a specific insult followed by an inflammatory response and when combined with other contributing factors (eg, hypercoagulability, vascular endothelial injury, hemodynamic changes) create favorable conditions for thrombosis. Diagnosis: Development of thrombosis in small animals remains challenging to demonstrate. Compatible clinical signs, the presence of known risk factors, and supporting diagnostic tests may be highly suggestive of the development of thrombosis. Therapy: Therapeutic recommendations in accordance with the CURATIVE guidelines for dogs and cats are described in specific case vignettes presented. Discussion is centered on antithrombotic drug choices and dosing protocols, as outlined in Domains 2 and 3 of the CURATIVE guidelines. Where appropriate, guidelines related to therapeutic monitoring (Domain 4) and discontinuation of antithrombotics (Domain 5) were included. Prognosis: In small animals at risk of developing thrombosis, overall prognosis may be improved by following consensus‐based recommendations on the use of antithrombotics as outlined in the CURATIVE guidelines. Whether such interventions have any impact on outcome requires further investigation. [ABSTRACT FROM AUTHOR]

Objectives: To systematically review available evidence and establish guidelines related to the risk of developing thrombosis and the management of small animals with antithrombotics. Design: Standardized, systematic evaluation of the literature (identified by searching Medline via PubMed and CAB abstracts) was carried out in 5 domains (Defining populations at risk; Defining rational therapeutic use; Defining evidence‐based protocols; Refining and monitoring antithrombotic therapies; and Discontinuing antithrombotic therapies). Evidence evaluation was carried out using Population, Intervention, Comparison, Outcome generated within each domain questions to address specific aims. This was followed by categorization of relevant articles according to level of evidence and quality (Good, Fair, or Poor). Synthesis of these data led to the development of a series of statements. Consensus on the final guidelines was achieved via Delphi‐style surveys. Draft recommendations were presented at 2 international veterinary conferences and made available for community assessment, review, and comment prior to final revisions and publication. Settings: Academic and referral veterinary medical centers. Results: Over 500 studies were reviewed in detail. Worksheets from all 5 domains generated 59 statements with 83 guideline recommendations that were refined during 3 rounds of Delphi surveys. A high degree of consensus was reached across all guideline recommendations. Conclusions: Overall, systematic evidence evaluations yielded more than 80 recommendations for the treatment of small animals with or at risk of developing thrombosis. Numerous significant knowledge gaps were highlighted by the evidence reviews undertaken, indicating the need for substantial additional research in this field. [ABSTRACT FROM AUTHOR]

Objectives: To systematically review available evidence to determine when small animals at risk of thrombosis should be treated with antiplatelet agents and anticoagulants, which antiplatelet and anticoagulant agents are most effective, and when multimodal therapy is indicated. Design: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence (LOE) and quality (Good, Fair, or Poor), and development of consensus on conclusions via a Delphi‐style survey for application of the concepts to clinical practice. Draft recommendations were presented at 2 international veterinary conferences and made available for community assessment, review, and comment prior to final revisions and publication. Settings: Academic and referral veterinary medical centers. Results: Databases searched included Medline via PubMed and CAB abstracts. Twelve Population Intervention Comparison Outcome questions were devised and generated corresponding worksheets investigating indications for use of antithrombotic drugs in small animals. Seventy‐eight studies were reviewed in detail. Most studies assessed were experimentally controlled laboratory studies in companion animals (56 LOE 3) with smaller numbers of LOE 2 (1), LOE 4 (5), LOE 5 (6), and LOE 6 (4) studies assessed. Only 5 randomized controlled clinical trials were identified (LOE 1, Good–Fair). The 12 worksheets generated 21 guidelines with 17 guideline statements that were refined during 3 rounds of Delphi surveys. A high degree of consensus was reached across all guideline recommendations during the Delphi process. Conclusions: Overall, systematic evidence evaluations generated 2 strong recommendations, 19 weak recommendations (formulated as suggestions), 9 situations where the evidence was insufficient to make strong recommendations, and 8 situations where no relevant evidence was retrieved to aid guideline generation. Numerous significant knowledge gaps were highlighted by the evidence reviews undertaken, indicating the need for substantial additional research in this field. [ABSTRACT FROM AUTHOR]

Objective: The clinical diagnosis of disseminated intravascular coagulation (DIC) in dogs is challenging. It was hypothesized that dogs with laboratory abnormalities consistent with overt DIC have increased mortality and hence survival could be used to evaluate the performance of DIC scoring systems. Four DIC scoring systems were compared in clinically ill dogs: The International Society of Thrombosis and Haemostasis (ISTH) score; a previously published veterinary DIC score; a system using in‐house reference intervals (RIs) for coagulation assays; and the published veterinary DIC score modified by use of in‐house RI values. Design: Retrospective cohort study. Setting: University teaching hospital. Animals: Eight hundred four client‐owned dogs with underlying disorders associated with DIC. Interventions: None. Measurements and Main Results: Medical records were reviewed to identify dogs for which a coagulation panel consisting of coagulation times, D‐dimer concentration, antithrombin activity, fibrinogen concentration, and platelet count had been analyzed. Four methods for overt DIC scoring were then applied, and the ability of these scores to predict mortality was evaluated. Use of institution RIs for diagnosis of overt DIC provided the most accurate prognostic assessment. A score based on abnormalities in 3 of 6 parameters to identify overt DIC was 72.7% sensitive and 80.9% specific for mortality and was accurate in 78.4% of cases. The mortality rate of dogs diagnosed with overt DIC via this method was 62.5%, compared to 12.9% in the dogs not in overt DIC, a relative risk of nonsurvival of 4.84 (95% confidence interval 3.80–6.16). Conclusions: In dogs at‐risk for DIC, an in‐house RI scoring system accurately predicted mortality. With further prospective validation, this system holds promise as a diagnostic tool for consistent characterization of overt DIC in clinical studies and clinical practice. [ABSTRACT FROM AUTHOR]

Objective: To investigate the use of plasma cell‐free DNA (cfDNA) and nucleosome concentrations as prognostic biomarkers in canine sepsis. Design: Prospective, observational cohort study conducted from June 2015 to February 2016. Setting: University teaching hospital. Animals: Forty‐five dogs with sepsis, 10 dogs with nonseptic systemic inflammatory response syndrome (nSIRS), and 15 healthy controls were consecutively enrolled and followed to hospital discharge. Patients were eligible for enrollment if they met ≥2 SIRS criteria and had a documented or highly suspected bacterial infection. Dogs <3 kg or with a known coagulopathy were excluded. Interventions: None. Measurements and Main Results: Acute Patient Physiology and Laboratory Evaluation scores (APPLE) were calculated and outcomes recorded. Plasma cfDNA was measured using a benchtop fluorimeter. Plasma nucleosome concentrations were determined by ELISA. Plasma nucleosome and cfDNA concentrations in dogs with sepsis or nSIRS were compared to those of healthy controls and cfDNA concentrations in septic dogs with and without bacteremia were compared. Associations between cfDNA concentrations and nucleosomes, leukocyte count, neutrophil count, and APPLE scores were evaluated. For septic dogs, cfDNA concentrations relative to neutrophil count and nucleosome concentrations in survivors and nonsurvivors were compared. Alpha was set at 0.05. cfDNA concentrations were significantly higher in dogs with sepsis or nSIRS compared to healthy controls (P < 0.0001 and P = 0.0034, respectively). Nucleosome concentrations were significantly higher in dogs with sepsis compared to healthy controls (P = 0.007). There was limited association between cfDNA and nucleosome concentrations (rs = 0.266), and no association between cfDNA concentration and leukocyte count, neutrophil count, and APPLEfull scores. Concentrations of cfDNA were positively correlated with APPLEfast score (rs = 0.335, P = 0.025); however, cfDNA concentrations were significantly higher in dogs with bacteremia (P = 0.0299). In dogs with sepsis, cfDNA concentrations relative to neutrophil count were significantly higher in nonsurvivors than in survivors (P = 0.008). Conclusions: In dogs with sepsis, high cfDNA concentrations relative to neutrophil count are associated with nonsurvival. Point‐of‐care cfDNA measurement may aid identification of bacteremia. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To evaluate whether cell‐free DNA (cfDNA) concentrations are increased in dogs with exertional rhabdomyolysis and whether concentrations are correlated with serum myoglobin concentration and creatine kinase activity. Design: Observational cohort study. Setting: Yukon Quest 1,000‐mile International Sled Dog Race 2015. Animals: Twelve normal competitive sled dogs; 5 dogs with rhabdomyolysis. Interventions: None. Measurements and Main Results: Blood was collected from all confirmed cases of exertional rhabdomyolysis and compared to the winning team at the midrace point. Results indicate that median cfDNA did not increase, but decreased by the race finish (prerace = 314.2 ng/mL versus midrace = 283.7 ng/mL versus postrace = 249.5 ng/mL). There were no rises in median cfDNA in dogs with rhabdomyolysis (255 ng/mL) negating its potential utility as a measure of acute skeletal muscle compromise. In contrast, myoglobin concentration and creatine kinase activity at the midrace point for normal dogs were significantly lower than dogs with rhabdomyolysis. Values for myoglobin and creatine kinase were strongly positively correlated (R = 0.91). Conclusions: cfDNA is not a useful biomarker for exertional rhabdomyolysis in contrast to myoglobin and creatine kinase. Further evaluation of timing and clinical signs suggests that exertional rhabdomyolysis occurs early in endurance activities. Among the dogs with rhabdomyolysis, the dog that demonstrated clinical signs had the highest serum creatine kinase activity and myoglobin concentration. [ABSTRACT FROM AUTHOR]

Abstract: Objectives: To disseminate information regarding the annual pass rates for the American College of Veterinary Emergency and Critical Care (ACVECC) certifying examination. To compare the first‐time pass rates (FTPR) of ACVECC residents trained in academic and private practice settings. Design: Retrospective study. Setting: ACVECC examination. Animals: None. Interventions: None. Measurements and Main Results: Anonymized ACVECC examination performance data from 2010–2015 inclusive were analyzed. Overall pass rates and FTPR were calculated for all candidates and categorized by type of residency training program. The overall pass rate for all candidates was 64.3%. The median pass rate for the 6‐year period was 63.8% [IQR 59.3–67.3%]. The FTPR for residents trained in academic programs was significantly higher than for residents trained in private practice (77.1% vs 47.2%, P < 0.0001). When residents were subdivided by species‐focus of training program, there was no significant difference between academic versus private practice training programs for large‐animal candidates (P = 0.2), but there remained a significant difference between residency training programs for small‐animal candidates (P < 0.0001). Conclusions: Between 2010 and 2015 residents trained in academic training programs were significantly more likely to pass the ACVECC certifying examination compared to those trained in private practice training programs. The causes of this difference are uncertain, are likely multifactorial and warrant further investigation. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To establish and compare the repeatability and reproducibility of activated thromboelastography (TEG) and thromboelastometry (ROTEM) assays. Design: Multicenter in vitro test standardization. Setting: Veterinary academic centers. Animals: Test samples were obtained from normal, healthy dogs. Sixty identical 5 mL aliquots of canine platelet‐rich plasma collected by apheresis, frozen in 6% dimethyl sulfoxide, were tested initially. Sixty identical 6 mL aliquots of canine fresh frozen plasma with admixed cryoprecipitate were subsequently evaluated. Interventions: None. Measurements and Main Results: Frozen study samples, quality controls, reagents, and consumables were distributed to participating centers (7 TEG and 3 ROTEM). TEG centers analyzed study samples with kaolin and tissue factor activated assays; ROTEM centers ran proprietary ellagic acid activated and tissue factor activated assays. All machines underwent quality control prior to sample analysis. Within‐ and between‐center coefficients of variation (CVs) were calculated and compared using Mann–Whitney tests and calculation of intraclass correlation coefficients. Within and between centers, individual parameters for both TEG and ROTEM assays were comparable. Both within‐center and between‐center CVs varied markedly (0.7–120.5% and 1.4–116.5%, respectively) with assay type, instrument, and parameter. CVs for equivalent parameters were not significantly different between the 2 platforms. Intraclass correlation coefficients suggested moderate agreement between centers. In general, individual parameter CVs for platelet‐rich plasma samples were lower in TEG centers, while CVs for canine fresh frozen plasma with admixed cryoprecipitate samples were lower in ROTEM centers. Conclusions: More variation within and between centers was identified than anticipated, but some parameters such as alpha angle were repeatable and reproducible. Sample types for future multicenter standardization efforts will require further optimization and may need to be adapted separately to each platform. Individual centers using viscoelastic tests for evaluation and management of clinical patients should take steps to minimize preanalytical and analytical sources of variation. [ABSTRACT FROM AUTHOR]

Objectives To determine if cell-free DNA (cfDNA) was identifiable in canine plasma, to evaluate 3 techniques for the measurement of plasma cfDNA concentrations in dogs presented to an emergency service, and to compare the plasma cfDNA concentrations of healthy dogs to those with sepsis, trauma, and neoplasia. Design Retrospective study of banked canine plasma samples collected between May 2014 and December 2014. Setting Dogs presented to the emergency service of a university veterinary teaching hospital. Animals Plasma cfDNA was measured on residual plasma samples obtained from 15 dogs with sepsis, 15 dogs with moderate-severe trauma, 15 dogs diagnosed with a sarcoma. Plasma cfDNA was also measured in 15 healthy dogs. Interventions None. Measurements and Main Results Assay linearity, repeatability, and reproducibility were evaluated. Quantification of cfDNA was performed in duplicate on diluted citrated plasma and following DNA purification using 2 fluorescence assays (SYBR-Gold; Quant-iT) and by ultraviolet absorbance spectroscopy. Fluorescence intensities (FIs) were converted to cfDNA concentrations using standard curves. Median FI values and cfDNA concentrations were compared to healthy controls using the Kruskal-Wallis test, with adjustment for multiple comparisons. Alpha was set at 0.05. Both assays had excellent linearity, and acceptable repeatability and reproducibility. Compared to controls, plasma cfDNA concentrations were significantly increased in dogs with sepsis or moderate-severe trauma with both assays ( P ≤ 0.003). Dogs with neoplasia had significantly increased cfDNA concentrations with the Quant-iT assay only ( P = 0.003). When measurements were performed on purified DNA, only dogs with moderate-severe trauma had significantly increased cfDNA concentrations ( P < 0.001; SYBR-Gold assay). Conclusions cfDNA can be readily identified in canine plasma using 2 fluorescence assays. DNA extraction offers no advantage over direct measurement. Compared to healthy controls, dogs with sepsis or moderate-severe trauma have significantly increased plasma cfDNA concentrations. [ABSTRACT FROM AUTHOR]

The article focuses on a collaboration formed to classify thrombosis risk in companion animals and to establish guidelines for the management of small animals with antithrombotics. According to the author, conditions such as protein losing enteropathy, hypothyroidism and dirofilariasis could be associated with the development of thrombosis.

Rho GTPases are critical for platelet function. Although the roles of RhoA, Rac and Cdc42 are characterized, platelets express other Rho GTPases, whose activities are less well understood. This review summarizes our understanding of the roles of platelet Rho GTPases and focuses particularly on the functions of Rif and RhoG. In human platelets, Rif interacts with cytoskeleton regulators including formins mDia1 and mDia3, whereas RhoG binds SNARE-complex proteins and cytoskeletal regulators ELMO and DOCK1. Knockout mouse studies suggest that Rif plays no critical functions in platelets, likely due to functional overlap with other Rho GTPases. In contrast, RhoG is essential for normal granule secretion downstream of the collagen receptor GPVI. The central defect in RhoG-/- platelets is reduced dense granule secretion, which impedes integrin activation and aggregation and limits platelet recruitment to growing thrombi under shear, translating into reduced thrombus formation in vivo. Potential avenues for future work on Rho GTPases in platelets are also highlighted, including identification of the key regulator for platelet filopodia formation and investigation of the role of the many Rho GTPase regulators in platelet function in both health and disease. [ABSTRACT FROM AUTHOR]

A response from the authors of the article about clinical trials for the treatment of dogs with immune-mediated hemolytic anemia (IMHA) is presented.

Objective To systematically examine the evidence on nontraditional uses of viscoelastic coagulation monitoring in veterinary species. Design Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence and quality, and development of consensus on conclusions for application of the concepts to clinical practice. Setting Academic and referral veterinary medical centers. Results Databases searched included Medline, CAB abstracts, and Google Scholar. Conclusions Nontraditional assays identified included thrombelastography (TEG)-PlateletMapping (PM), functional fibrinogen assessment, and rapid-TEG (r-TEG). Direct veterinary evidence was found for only the ADP-activated PM, which appears to generate valid data in dogs but not cats or horses. Arachidonic acid activated PM shows high variability and requires further assessment and validation in veterinary species. Functional fibrinogen assays may be performed in veterinary species but may require modification due to species differences in response to abciximab. While tissue factor (TF)-activated TEG has been well described in the veterinary literature, the specific r-TEG assay has not been assessed, but presumably would be effective for generating TEG tracings and values for maximum amplitude and angle in shorter periods of time than some traditional assays. [ABSTRACT FROM AUTHOR]

Objective To systematically examine the evidence relating to the performance of rotational viscoelastic testing in companion animals, to develop assay guidelines, and to identify knowledge gaps. Design Multiple questions were considered within 5 parent domains, specifically system comparability, sample handling, assay activation and test protocol, definitions and data reporting, and nonstandard assays. Standardized, systematic evaluation of the literature was performed. Relevant articles were categorized according to level of evidence and assessed for quality. Consensus was developed regarding conclusions for application of concepts to clinical practice. Setting Academic and referral veterinary medical centers. Results Databases searched included Medline, Commonwealth Agricultural Bureaux abstracts, and Google Scholar. Worksheets were prepared evaluating 28 questions across the 5 domains and generating 84 assay guidelines. Conclusions Evidence-based guidelines for the performance of thromboelastography in companion animals were generated through this process. Some of these guidelines are well supported while others will benefit from additional evidence. Many knowledge gaps were identified and future work should be directed to address these gaps and to objectively evaluate the impact of these guidelines on assay comparability within and between centers. [ABSTRACT FROM AUTHOR]

Objective To systematically examine the evidence on system comparability between the thromboelastography and the rotational thromboelastometry viscoelastic point-of-care instruments and to identify knowledge gaps. Design Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence and quality, and development of consensus on conclusions for application of the concepts to clinical practice. Setting Academic and referral veterinary medical centers. Results Medline via PubMed, CAB abstracts, and Google Scholar were searched. A total of 8 relevant articles were chosen, none were in support of the question, 1 was neutral to the question (level of evidence [LOE] 6, Poor), and 7 were in opposition to the question (LOE 3 Good; LOE 6 Good; LOE 6 Fair; LOE 6 Poor). Conclusions Results from the 2 analyzers are not directly comparable and extrapolation of the results from one machine to the other should be avoided. Standardization of the preanalytical variables (eg, blood collection, holding time, and temperature during holding) is strongly recommended. It is recommended that each site create their own 'site specific' reference values for each machine and that test samples be compared only to the standardized reference values established at that center. Start-up and consumable costs vary between countries and local comparisons should be performed. Decisions should be made based on the expected use of the machine and if multiple operators will be using it. [ABSTRACT FROM AUTHOR]

Objective To systematically examine the evidence on activating agents and test protocols for the thrombelastography (TEG) and rotational thrombelastometry (ROTEM) viscoelastic point-of-care instruments and to identify knowledge gaps. Design Ten questions were considered, the primary question addressed the use of activating agents and secondary questions addressed assay temperature, length of analysis, pipetting, sample volume, reproducibility, and quality controls. Standardized, systematic evaluation of the literature was performed. Relevant articles were categorized according to level of evidence (LOE). Consensus was developed regarding conclusions for application of concepts to clinical practice. Setting Academic and referral veterinary medical centers. Results PubMed and CAB abstracts were searched. Twenty papers were initially identified concerning the primary question; 16 were in support of the questions (LOE 2 Good, LOE 3 Good, LOE 5 Good, LOE 6 Good, LOE 5 Fair, LOE 6 Fair); and 4 were neutral (LOE 3 Good, LOE 6 Good, LOE Fair, LOE 5 Fair). Additional papers were evaluated post hoc during manuscript preparation. Conclusions Overall, there is a body of evidence from veterinary and human medicine that strongly suggests that TEG or ROTEM assays using citrated samples that employ an activator have significantly lower inherent variability than those that use recalcification alone. There is also strong evidence in dogs, cats, and humans that the results obtained using different activators are not directly comparable. There is no evidence to suggest that any one activating agent is superior to another for all patient populations, or drug monitoring indications. As such, use of more than one assay for complete thromboelastographic evaluation of a patient's coagulation system may be warranted. Standardization of the concentrations of activators would be beneficial. [ABSTRACT FROM AUTHOR]

Rho GTPases such as Rac, RhoA, and Cdc42 are vital for normal platelet function, but the role of RhoG in platelets has not been studied. In other cells, RhoG orchestrates processes integral to platelet function, including actin cytoskeletal rearrangement and membrane trafficking. We therefore hypothesized that RhoG would play a critical role in platelets. Here, we show that RhoG is expressed in human and mouse platelets and is activated by both collagen-related peptide (CRP) and thrombin stimulation. We used RhoG-/- mice to study the function of RhoG in platelets. Integrin activation and aggregation were reduced in RhoG-/- platelets stimulated by CRP, but responses to thrombin were normal. The central defect in RhoG-/- platelets was reduced secretion from α-granules, dense granules, and lysosomes following CRP stimulation. The integrin activation and aggregation defects could be rescued by ADP co-stimulation, indicating that they are a consequence of diminished dense granule secretion. Defective dense granule secretion in RhoG-/- platelets limited recruitment of additional platelets to growing thrombi in flowing blood in vitro and translated into reduced thrombus formation in vivo. Interestingly, tail bleeding times were normal in RhoG-/- mice, suggesting that the functions of RhoG in platelets are particularly relevant to thrombotic disorders. [ABSTRACT FROM AUTHOR]

Background: Formation of filopodia and other shape change events are vital for platelet hemostatic function. The mechanisms regulating filopodia formation by platelets are incompletely understood however. In particular the small GTPase responsible for initiating filopodia formation by platelets remains elusive. The canonical pathway involving Cdc42 is not essential for filopodia formation in mouse platelets. The small GTPase Rif (RhoF) provides an alternative route to filopodia generation in other cell types and is expressed in both human and mouse platelets. Hypothesis/Objective: We hypothesized that Rif might be responsible for generating filopodia by platelets and generated a novel knockout mouse model to investigate the functional role of Rif in platelets. Methodology/Principal Findings: Constitutive RhoF-/- mice are viable and have normal platelet, leukocyte and erythrocyte counts and indices. RhoF-/- and spread normally on various agonist surfaces in static conditions and under arterial shear. In addition, RhoF-/- platelets have normal actin dynamics, are able to activate and aggregate normally and secrete from alpha and dense granules in response to collagen related peptide and thrombin stimulation. Conclusions: The small GTPase Rif does not appear to be critical for platelet function in mice. Functional overlap between Rif and other small GTPases may be responsible for the non-essential role of Rif in platelets. [ABSTRACT FROM AUTHOR]

Objective To review the receptors and signal transduction pathways involved in platelet plug formation and to highlight links between platelets, leukocytes, endothelium, and the coagulation system. Data Sources Original studies, review articles, and book chapters in the human and veterinary medical fields. Data Synthesis Platelets express numerous surface receptors. Critical among these are glycoprotein VI, the glycoprotein Ib- IX- V complex, integrin αIIbβ3, and the G-protein-coupled receptors for thrombin, ADP, and thromboxane. Activation of these receptors leads to various important functional events, in particular activation of the principal adhesion receptor αIIbβ3. Integrin activation allows binding of ligands such as fibrinogen, mediating platelet-platelet interaction in the process of aggregation. Signals activated by these receptors also couple to 3 other important functional events, secretion of granule contents, change in cell shape through cytoskeletal rearrangement, and procoagulant membrane expression. These processes generate a stable thrombus to limit blood loss and promote restoration of endothelial integrity. Conclusions Improvements in our understanding of how platelets operate through their signaling networks are critical for diagnosis of unusual primary hemostatic disorders and for rational antithrombotic drug design. [ABSTRACT FROM AUTHOR]

The article discusses coming up with an effective immunosuppressive therapy for dogs with immune-mediate hemolytic anemia (IMHA), in which topics discussed include the use of antiplatelet agents for thromboprophylaxis in IMHA and the use of anticoagulants or multiple drug depending on disease severity. Also mentioned is the efficacy of clopidogrel as the standard thromboprophylaxis in an random clinical trial (RCT) protocol.

Objective– To review the pathophysiology, clinical signs, diagnosis, and treatment of pulmonary thromboembolism (PTE) in small animals. Data Sources– Human and veterinary clinical studies, reviews, texts, and recent research in canine and feline PTE diagnosis and thromboembolic therapeutics. Human Data Synthesis– In humans, clinical probability assessment and point-of-care D-dimer-based algorithms are widely used. Computed tomography pulmonary angiography is the gold standard for PTE diagnosis in humans. Echocardiography is increasingly used for bedside assessment of affected patients. In low-risk human patients anticoagulants alone are recommended while patients with cardiogenic shock are treated with thrombolytics followed by anticoagulation. Veterinary Data Synthesis– PTE is associated with numerous predisposing conditions causing hypercoagulability, blood flow stasis, or endothelial injury. Identifying at-risk patients is key to diagnosis in small animals. Thromboelastography provides a method for identifying hypercoagulable patients. Computed tomography pulmonary angiography may replace selective pulmonary angiography as the imaging technique of choice for PTE diagnosis. PTE therapy consists of supportive treatment combined with appropriate, individualized thromboembolic pharmacotherapy for acute treatment and chronic management. Thrombolytic therapy for PTE remains controversial but may be indicated in hemodynamically unstable acute PTE. Thromboprophylaxis in specific conditions is rational although evidence of efficacy is limited. Prognosis depends upon degree of cardiopulmonary compromise and patient response to therapy. Mortality rates in small animals are unknown. Conclusions– New diagnostic techniques and advances in therapy offer significant potential for improvements in the identification and treatment of PTE in small animals. Further study must be directed to validating new diagnostic modalities and evaluating therapeutic regimes. [ABSTRACT FROM AUTHOR]

Complement-mediated intravascular hemolysis occurs in canine immune-mediated hemolytic anemia (IMHA). Complement inhibitors might enhance treatment of this disease. Dimers of acetylsalicylic acid such as 5,5'-methylenebis(2-acetoxybenzoic acid) (DAS) have been reported to inhibit complement. This study aimed to characterize the pharmacokinetics and safety profile of a single 3 mg/kg IV dose of DAS in 6 healthy mixed-breed dogs. Serum concentrations of DAS and its primary metabolites were measured by liquid chromatography-tandem mass spectrometry at baseline and at 5, 10 and 30 min, and 1, 2, 4, 6, 8, 12, 18 and 24 h post-administration. Additional blood samples were collected 7 and 14 days after drug administration. Complete blood counts, serum chemistry panels, C-reactive protein measurements, coagulation testing and cytokine analyses were used for safety monitoring. Following IV administration of 3 mg/kg DAS, the estimated mean maximum plasma concentration was 54,709 ng/mL. Pharmacokinetic modeling suggested that DAS was eliminated with a half-life value of 8.1 h, equivalent to a clearance of 6.93 L/hr kg and a volume of distribution of 56 mL/kg. Plasma concentrations of the metabolites were measured rapidly (within 15−60 min for M1 and M2 respectively). Overall, the relative exposure to M1 and M2 suggest significant biotransformation of DAS occurred, but DAS was the most abundant circulating species. No adverse clinical reactions were noted following DAS administration and safety studies suggested DAS caused no inflammatory response or coagulation disturbance. Further clinical evaluation of DAS is warranted. [ABSTRACT FROM AUTHOR]

COLLOID fluid therapy is indicated to treat hypovolaemia and aid the maintenance of plasma volume and intravascular colloid osmotic pressure. The numerous types, preparations and concentrations of colloid solutions available all have varying indications, pharmacokinetics and pharmacodynamics. Selection of a particular product should be based on a sound understanding of these individual characteristics, including their benefits, limitations and side effects. This article describes the properties of commonly used colloid solutions and their indications. Part 1, published in January 2008 (In Practice, volume 30, pp 16-19), discussed patient assessment and the principles of fluid therapy in small animals. Part 2, published in the last issue (In Practice, February 2008, volume 30, pp 85-91), reviewed crystalloid solutions. [ABSTRACT FROM PUBLISHER]

CRYSTALLOID fluids contain water, electrolytes and non-electrolyte solutes, and can enter all body fluid compartments. They can be used to replace fluid deficits or to provide for ongoing losses, and play an important role in small animal veterinary practice. Replacement solutions are required for patients with deficits of either electrolytes, water or, most commonly, both. Maintenance solutions are indicated once an animal has been stabilised to provide for normal fluid and electrolyte demands, or if patients have solely pure water loss. Replacement solutions can be used as maintenance solutions provided they are supplemented with potassium and the animal is capable of excreting the extra sodium. This is possible in most cases, but extra care must be taken with patients with compensated congestive heart failure or those with hyper- or hyponatraemia, and in situations of pure water loss. This article describes the properties of commonly used crystalloid solutions and their indications. An article in the March issue of In Practice will review colloid solutions. Part 1, published in the last issue (, January 2008, volume 30, pp 16-19), discussed patient assessment and the principles of fluid therapy in small animals. [ABSTRACT FROM PUBLISHER]

THE administration of fluid therapy is commonly used in veterinary medicine to combat dehydration, hypovolaemia and hypoperfusion, to maintain intravascular volume and osmotic pressure, and to correct electrolyte imbalances. An understanding of the physiology of body fluids is important to ensure that the most appropriate fluid is chosen for a given situation. This article, the first in a series of three, describes the principles of fluid therapy and highlights the key aspects of patient assessment. Articles in the February and March issues of will discuss the individual properties of crystalloid and colloid solutions, respectively. [ABSTRACT FROM PUBLISHER]

There is growing recognition of the importance of nutritional factors in the maintenance of bone and joint health, and that nutritional imbalance combined with endocrine abnormalities may be involved in the pathogenesis of osteoarthritis (OA) and osteochondritis dissecans (OCD). Despite this, dietary programs have played a secondary role in the management of these connective tissue disorders. Articular cartilage is critically dependent upon the regular provision of nutrients (glucose and amino acids), vitamins (particularly vitamin C), and essential trace elements (zinc, magnesium, and copper). Therefore, dietary supplementation programs and nutraceuticals used in conjunction with non-steroidal, anti-inflammatory drugs (NSAIDs) may offer significant benefits to patients with joint disorders, such as OA and OCD. This article examines the available clinical evidence for the efficacy of nutraceuticals, antioxidant vitamin C, polyphenols, essential fatty acids, and mineral cofactors in the treatment of OA and related joint disorders in humans and veterinary species. This article also attempts to clarify the current state of knowledge. It also highlights the need for additional targeted research to elucidate the changes in nutritional status and potential alterations to the expression of plasma membrane transport systems in synovial structures in pathophysiological states, so that current therapy and future treatments may be better focused. [ABSTRACT FROM AUTHOR]

Background Hypothesis Animals Methods Results Conclusions and Clinical Importance Comparative pharmacokinetics and pharmacodynamics (PK/PD) of apixaban and rivaroxaban have not been studied in dogs and the propensity of these drugs to cause hypercoagulability after discontinuation is unknown.Compare the PK/PD of clinical dosing regimens of PO apixaban and rivaroxaban administered repeatedly to healthy dogs and assess the effect of abrupt drug discontinuation on coagulation.Six University‐owned, purpose‐bred, middle‐aged, mixed‐breed dogs (4 male, 2 female).Dogs were given apixaban or rivaroxaban PO at 0.5 mg/kg q12h for 7 days with a 14‐day washout period between drugs. Plasma drug concentrations were quantitated, and anticoagulant effects were measured using clotting times, calibrated anti‐Xa bioactivity assays, and measurements of thrombin generation. The potential for rebound hypercoagulability was assessed by measuring D‐dimers, thrombin‐antithrombin (TAT) complexes, and antithrombin activity after drug discontinuation.Plasma drug concentrations and anti‐Xa bioactivities were closely correlated for both drugs, but drug concentrations varied considerably among dogs, despite consistent dose regimens. Thrombin generation variables were significantly correlated with the anti‐Xa bioactivity of both drugs and no significant differences in the effects of apixaban and rivaroxaban on thrombin generation were observed. Drug discontinuation had no effect on D‐dimer concentrations. The concentration of TAT complexes decreased after apixaban discontinuation and did not change after rivaroxaban discontinuation.Repeated PO administration of apixaban or rivaroxaban to healthy dogs produced comparable anticoagulant effects measured by inhibition of thrombin formation. Rebound hypercoagulability after drug discontinuation was not observed and weaning of these drugs in clinical patients might not be necessary. [ABSTRACT FROM AUTHOR]

Background: Immune thrombocytopenia (ITP) is a common cause of severe thrombocytopenia in dogs. The pathogenesis of nonassociative, primary ITP (pITP) appears complex, with ill‐defined thrombopoietic response. Objectives: Develop an immunoassay to measure plasma canine thrombopoietin (TPO) concentration and characterize TPO concentrations in dogs with pITP. Animals: Forty‐one healthy dogs, 8 dogs in an induced ITP model (3 control, 5 ITP), and 58 pITP dogs. Methods: Recombinant canine TPO (rcTPO) was purchased and its identity confirmed by mass spectrometry. Monoclonal antibodies were raised to rcTPO and used to configure a sandwich ELISA using streptavidin‐biotin detection. Assay performance, coefficients of variability, and healthy dog plasma TPO reference interval (RI) were determined, followed by assay of ITP samples. Results: Assay dynamic range was 15 pg/mL (lower limit of detection) to 1000 pg/mL TPO, with limit of quantitation of 62 pg/mL. Plasma TPO RI was 0 to 158 pg/mL, with plasma TPO <62 pg/mL for 35/41 healthy dogs. All dogs with induced ITP developed marked increases in plasma TPO concentration. Peak values ranged from 515 to >6000 pg/mL. In contrast, only 2/58 pITP dogs had TPO values above RI. Conclusions and Clinical Importance: Plasma TPO concentration is paradoxically low at diagnosis for most dogs with pITP. This finding suggests that ineffective thrombopoiesis contributes to thrombocytopenia in pITP dogs and supports evaluating TPO receptor agonist treatment as used for pITP in humans. The TPO assay provides a new tool to study thrombopoiesis in pITP and other thrombocytopenic syndromes in dogs. [ABSTRACT FROM AUTHOR]

The article discusses the variability in veterinary thromboelastography.

Immune thrombocytopenia (ITP) is the most common acquired primary hemostatic disorder in dogs. Immune thrombocytopenia less commonly affects cats but is an important cause of mortality and treatment‐associated morbidity in both species. Immune thrombocytopenia remains a diagnosis of exclusion for which diagnostic guidelines are lacking. Primary, or non‐associative, ITP refers to autoimmune platelet destruction. Secondary, or associative, ITP arises in response to an underlying disease trigger. However, evidence for which comorbidities serve as ITP triggers has not been systematically evaluated. To identify key diagnostic steps for ITP and important comorbidities associated with secondary ITP, we developed 12 Population Evaluation/Exposure Comparison Outcome (PECO) format questions. These questions were addressed by evidence evaluators utilizing a literature pool of 287 articles identified by the panelists using a structured search strategy. Evidence evaluators, using panel‐designed templates and data extraction tools, summarized evidence and created guideline recommendations that then were integrated by diagnosis and comorbidity domain chairs. The revised PECO responses underwent a Delphi survey process to reach consensus on final guidelines. A combination of panel expertise and PECO responses were employed to develop algorithms for diagnosis of ITP in dogs and cats, which also underwent 4 iterations of Delphi review. Comorbidity evidence evaluators employed an integrated measure of evidence (IME) tool to determine evidence quality for each comorbidity; IME values combined with evidence summaries for each comorbidity were integrated to develop ITP screening recommendations, which also were subjected to Delphi review. Commentary was solicited from multiple relevant professional organizations before finalizing the consensus. The final consensus statement provides clinical guidelines for the diagnosis of, and underlying disease screening for, ITP in dogs and cats. The systematic consensus process identified numerous knowledge gaps that should guide future studies. This statement is a companion manuscript to the ACVIM Consensus Statement on the Treatment of Immune Thrombocytopenia. [ABSTRACT FROM AUTHOR]

Objective: To discuss the definitions of sepsis in human and veterinary medicine. Design: International, multicenter position statement on the need for consensus definitions of sepsis in veterinary medicine. Setting: Veterinary private practice and university teaching hospitals. Animals: Dogs and cats. Interventions: None. Measurements and Main Results: Sepsis is a life‐threatening condition associated with the body's response to an infection. In human medicine, sepsis has been defined by consensus on 3 occasions, most recently in 2016. In veterinary medicine, there is little uniformity in how sepsis is defined and no consensus on how to identify it clinically. Most publications rely on modified criteria derived from the 1991 and 2001 human consensus definitions. There is a divergence between the human and veterinary descriptions of sepsis and no consensus on how to diagnose the syndrome. This impedes research, hampers the translation of pathophysiology insights to the clinic, and limits our abilities to optimize patient care. It may be time to formally define sepsis in veterinary medicine to help the field move forward. In this narrative review, we present a synopsis of prior attempts to define sepsis in human and veterinary medicine, discuss developments in our understanding, and highlight some criticisms and shortcomings of existing schemes. Conclusions: This review is intended to serve as the foundation of current efforts to establish a consensus definition for sepsis in small animals and ultimately generate evidence‐based criteria for its recognition in veterinary clinical practice. [ABSTRACT FROM AUTHOR]

Domestic dogs share the same environment as humans, and they represent a valuable animal model to study naturally-occurring human disease. Platelet proteomics holds promise for the discovery of biomarkers that capture the contribution of platelets to the pathophysiology of many disease states, however, canine platelet proteomic studies are lacking. Our study objectives were to establish a protocol for proteomic identification and quantification of the thrombin-activated canine platelet secretome (CAPS), and to compare the CAPS proteins to human and murine platelet proteomic data. Washed platelets were isolated from healthy dogs, and stimulated with saline (control) or gamma-thrombin (releasate). Proteins were separated by SDS-page, trypsin-digested and analyzed by liquid chromatography and tandem mass spectrometry (MS). CAPS proteins were defined as those with a MS1-abundance ratio of two or more for releasate vs. unstimulated saline control. A total of 1,918 proteins were identified, with 908 proteins common to all dogs and 693 characterized as CAPS proteins. CAPS proteins were similar to human and murine platelet secretomes and were highly represented in hemostatic pathways. Differences unique to CAPS included replacement of platelet factor 4 with other cleavage products of platelet basic protein (e.g. interleukin-8), novel proteins (e.g. C-C motif chemokine 14), and proteins in relatively high (e.g. protease nexin-1) or low (e.g. von Willebrand factor) abundance. This study establishes the first in-depth platelet releasate proteome from healthy dogs with a reference database of 693 CAPS proteins. Similarities between CAPS and the human secretome confirm the utility of dogs as translational models of human disease, but we also identify differences unique to canine platelets. Our findings provide a resource for further investigations into disease-related CAPS profiles, and for comparative pathway analyses of platelet activation among species. [ABSTRACT FROM AUTHOR]

Objectives: To systematically examine the evidence for use of a specific protocol (dose, frequency, route) of selected antithrombotic drugs, in comparisons to no therapy or to other antithrombotic therapies, to reduce the risk of complications or improve outcomes in dogs and cats at risk for thrombosis. Design: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence (LOE) and quality (Good, Fair, or Poor), and development of consensus on conclusions via a Delphi‐style survey for application of the concepts to clinical practice. Settings: Academic and referral veterinary medical centers. Results: Databases searched included Medline via PubMed and CAB abstracts. Eight different antithrombotic drugs were investigated using a standardized Patient, Intervention, Comparison, Outcome (PICO) question format both for dogs and cats, including aspirin, clopidogrel, warfarin, unfractionated heparin (UFH), dalteparin, enoxaparin, fondaparinux, and rivaroxaban, generating a total of 16 worksheets. Most studies identified were experimental controlled laboratory studies in companion animals (LOE 3) with only four randomized controlled clinical trials in companion animals (LOE 1). Conclusions: Overall, evidence‐based recommendations concerning specific protocols could not be formulated for most antithrombotic drugs evaluated, either because of the wide range of dosage reported (eg, aspirin in dogs) or the lack of evidence in the current literature. However, clopidogrel administration in dogs and cats at risk of arterial thrombosis, notably in cats at risk of cardiogenic thromboembolism, is supported by the literature, and specific protocols were recommended. Comparably, aspirin should not be used as a sole antithrombotic in cats with cardiomyopathy. Using the available safety profile information contained in the literature, the panel reached consensus on suggested dosage schemes for most antithrombotics. Significant knowledge gaps were highlighted, which will hopefully drive novel research. [ABSTRACT FROM AUTHOR]

Background: Awareness of prescribing practices helps identify opportunities to improve antibiotic use (AU). Objectives: To estimate AU prevalence in dogs and cats in U.S. veterinary teaching hospitals (VTHs) and identify antibiotic drugs commonly prescribed, indications for use, and evidence of bacterial infection. Animals: Medical record data were collected from dogs and cats examined at 14 VTHs. Methods: Data were collected from VTH medical records of dogs and cats examined by primary care, urgent care, emergency and critical care, internal medicine, and surgery services on a single day during August 13‐September 3, 2020. Data included signalment; clinical service; inpatient or outpatient status; clinical conditions; diagnostic tests; evidence of bacterial infection; intended reason for AU; name and route of antibiotics prescribed. Results: Of 883 dogs and cats, 322 (36.5%) were prescribed at least 1 antibiotic. Among 285 antibiotics administered systemically intended for treatment of infection, 10.9% were prescribed without evidence of infection. The most common class of antibiotics presribed for systemic administration was potentiated penicillin for dogs (115/346, 33.3%) and cats (27/80, 33.8%). For dogs and cats, first‐generation cephalosporins (93/346, 26.9% and 11/80, 13.8%, respectively) and fluoroquinolones (51/346, 14.7% and 19/80, 23.8%, respectively) was second or third most‐prescribed. Common AU indications included skin, respiratory, and urinary conditions, and perioperative use. Conclusions and Clinical Importance: Collaborative data collection provides a sustainable methodology to generate national AU prevalence estimates and bring attention to areas requiring additional research and detailed data collection. These efforts can also identify practice improvement opportunities in settings where future veterinarians are trained. [ABSTRACT FROM AUTHOR]

Abstract: Acid–base abnormalities are frequently encountered in veterinary emergency and critical care, but information regarding the prognostic value of these findings is limited. Several systems for analysing acid–base disturbances have been reported, but the prognostic abilities of these systems have not been compared in dogs. The objectives of this retrospective study were to determine if the commonly used acid–base interpretation methods (Henderson–Hasselbalch, Stewart and semi‐quantitative) have prognostic value, and to compare the performance of the three methods. Electronic medical records were searched to create a database containing point‐of‐care blood‐gas, electrolyte and serum chemistry values for 1024 dogs assessed at a university teaching hospital. Dogs with contemporaneous blood‐gas analysis, blood lactate and serum biochemistry samples were eligible for study, and only the first recorded analyses for each patient visit were included. Components of the Henderson–Hasselbalch, Stewart and semi‐quantitative methods were calculated. To assess prognostic ability and to compare analysis system performance, receiver‐operating characteristic (ROC) curves for survival to hospital discharge were created. Of the 1024 dogs identified, case fatality rate was 23.8%. Area under the ROC curve did not exceed 0.63 for any calculated variable. Performance of all three analysis systems was similar. While some acid–base abnormalities identified were associated with mortality, no individual abnormality or system output yielded sensitive and specific cut‐off values for mortality prediction, and no interpretation method outperformed the others. This study suggests that initial acid–base abnormalities have limited prognostic utility and that various analysis systems can be used to assess acid–base disturbances in critically ill dogs. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To examine the animal trauma triage (ATT) and modified Glasgow Coma Scale (mGCS) scores as predictors of mortality outcome (death or euthanasia) in injured dogs. Design: Observational cohort study conducted from September 2013 to March 2015 with follow‐up until death or hospital discharge. Setting: Nine veterinary hospitals including private referral and veterinary teaching hospitals. Animals: Consecutive sample of 3,599 dogs with complete data entries recruited into the Veterinary Committee on Trauma patient registry. Interventions: None. Measurements and Main Results: We compared the predictive power (area under receiver operating characteristic [AUROC]) and calibration of the ATT and mGCS scores to their components. Overall mortality risk was 7.3% (n = 264). Incidence of head trauma was 9.5% (n = 341). The ATT score showed a linear relationship with mortality risk. Discriminatory performance of the ATT score was excellent with AUROC = 0.92 (95% confidence interval [CI] 0.91 to 0.94) and pseudo R2 = 0.42. Each ATT score increase of 1 point was associated with an increase in mortality odds of 2.07 (95% CI = 1.94–2.21, P < 0.001). The “eye/muscle/integument” category of the ATT showed poor discrimination (AUROC = 0.55). When this component together with the skeletal and cardiac components were omitted from calculation of the overall score, there was no loss in discriminatory capacity (AUROC = 0.92 vs 0.91, P = 0.09) compared with the full score. The mGCS showed good performance overall, but performance improved when restricted to head trauma patients (AUROC = 0.84, 95% CI = 0.79–0.90, n = 341 vs 0.82, 95% CI = 0.79–0.85, n = 3599). The motor component of the mGCS showed the best predictive performance (AUROC = 0.79 vs 0.66/0.69); however, the full score performed better than the motor component alone (P = 0.002). When assessment was restricted to patients with head injury (n = 341), the ATT score still performed better than the mGCS (AUROC = 0.90 vs 0.84, P = 0.04). Conclusions: In external validation on a large, multicenter dataset, the ATT score showed excellent discrimination and calibration; however, a more parsimonious score calculated on only the perfusion, respiratory, and neurological categories showed equivalent performance. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about the possible glycol toxicity of dogs.

Sepsis is a diagnostic and therapeutic challenge and is associated with morbidity and a high risk of death. Metabolomic and lipidomic profiling in sepsis can identify alterations in metabolism and might provide useful insights into the dysregulated host response to infection, but investigations in dogs are limited. We aimed to use untargeted metabolomics and lipidomics to characterize metabolic pathways in dogs with sepsis to identify therapeutic targets and potential diagnostic and prognostic biomarkers. In this prospective observational cohort study, we examined the plasma metabolomes and lipidomes of 20 healthy control dogs and compared them with those of 21 client-owned dogs with sepsis. Patient data including signalment, physical exam findings, clinicopathologic data and clinical outcome were recorded. Metabolites were identified using an untargeted mass spectrometry approach and pathway analysis identified multiple enriched metabolic pathways including pyruvaldehyde degradation; ketone body metabolism; the glucose-alanine cycle; vitamin-K metabolism; arginine and betaine metabolism; the biosynthesis of various amino acid classes including the aromatic amino acids; branched chain amino acids; and metabolism of glutamine/glutamate and the glycerophospholipid phosphatidylethanolamine. Metabolites were identified with high discriminant abilities between groups which could serve as potential biomarkers of sepsis including 13,14-Dihydro-15-keto Prostaglandin A2; 12(13)-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid); and 9-HpODE (9-Hydroxyoctadecadienoic acid). Metabolites with higher abundance in samples from nonsurvivors than survivors included 3-(2-hydroxyethyl) indole, indoxyl sulfate and xanthurenic acid. Untargeted lipidomic profiling revealed multiple sphingomyelin species (SM(d34:0)+H; SM(d36:0)+H; SM(d34:0)+HCOO; and SM(d34:1D3)+HCOO); lysophosphatidylcholine molecules (LPC(18:2)+H) and lipophosphoserine molecules (LPS(20:4)+H) that were discriminating for dogs with sepsis. These biomarkers could aid in the diagnosis of dogs with sepsis, provide prognostic information, or act as potential therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Acute phase proteins (APP) may guide treatment of pneumonia in dogs but correlations with radiographic abnormalities are poorly characterized. Objectives: Develop a thoracic radiographic severity scoring system (TRSS), assess correlation of radiographic changes with APP concentrations, and compare time to APP and radiograph normalization with duration of antimicrobials treatment. Animals: Sixteen client‐owned dogs, 12 with aspiration pneumonia, and 4 with community‐acquired pneumonia. Methods: Concentrations of C‐reactive protein (CRP), serum amyloid A (SAA), and haptoglobin were measured on days 1, 3, 7, 14, 28, and 60 and orthogonal 2‐view thoracic radiographs were obtained on days 1, 7, 14, 28, and 60. Treatment was clinician‐guided and blinded to APP concentrations. Radiographic severity scores were assigned by blinded, randomized retrospective review by 2 board‐certified radiologists with arbitration by a third radiologist. Results: Median (interquartile range [IQR]) time to normalization of CRP (7 days [7‐14]) and SAA concentrations (7 days [7‐14]) were shorter than antimicrobial treatment duration (17.5 days [14.5‐33.5]; P =.001 and.002, respectively) and TRSS normalization (14 days [8.8‐52], P =.02 and.02, respectively). The CRP and SAA concentrations were positively correlated with TRSS (CRP rs, 0.643; SAA rs, 0.634; both P <.0001). Both CRP and SAA identified normal thoracic radiographs area under the curve (AUC) 0.873 and 0.817, respectively, both P <.0001. Interobserver agreement for TRSS assignment was moderate (κ,.499; P <.0001). Conclusion and Clinical Importance: Concentrations of CRP and SAA normalized before radiographic resolution and before clinicians discontinued antimicrobial treatment. The CRP and SAA concentrations may guide duration of antimicrobial treatment for dogs with pneumonia. [ABSTRACT FROM AUTHOR]

Objectives: To systematically review available evidence and establish guidelines related to the use of thrombolytics for the management of small animals with suspected or confirmed thrombosis. Design: PICO (Population, Intervention, Control, and Outcome) questions were formulated, and worksheets completed as part of a standardized and systematic literature evaluation. The population of interest included dogs and cats (considered separately) and arterial and venous thrombosis. The interventions assessed were the use of thrombolytics, compared to no thrombolytics, with or without anticoagulants or antiplatelet agents. Specific protocols for recombinant tissue plasminogen activator were also evaluated. Outcomes assessed included efficacy and safety. Relevant articles were categorized according to level of evidence, quality, and as to whether they supported, were neutral to, or opposed the PICO questions. Conclusions from the PICO worksheets were used to draft guidelines, which were subsequently refined via Delphi surveys undertaken by the Consensus on the Rational Use of Antithrombotics and Thrombolytics in Veterinary Critical Care (CURATIVE) working group. Results: Fourteen PICO questions were developed, generating 14 guidelines. The majority of the literature addressing the PICO questions in dogs is experimental studies (level of evidence 3), thus providing insufficient evidence to determine if thrombolysis improves patient‐centered outcomes. In cats, literature was more limited and often neutral to the PICO questions, precluding strong evidence‐based recommendations for thrombolytic use. Rather, for both species, suggestions are made regarding considerations for when thrombolytic drugs may be considered, the combination of thrombolytics with anticoagulant or antiplatelet drugs, and the choice of thrombolytic agent. Conclusions: Substantial additional research is needed to address the role of thrombolytics for the treatment of arterial and venous thrombosis in dogs and cats. Clinical trials with patient‐centered outcomes will be most valuable for addressing knowledge gaps in the field. [ABSTRACT FROM AUTHOR]